CD4+ T-cells are central to the development of effective adaptive immune responses; however, like other lymphocytes, CD4+ T-cells are susceptible to cellular senescence. Senescent T-cells are characterized by shortened telomeres, reduced proliferative capacity, as well as altered cytokine production, signaling pathways and a host of other functional defects. Based on our preliminary data, we hypothesize that HIV-1 infection leads to accelerated senescence within the naive CD4+ T-cell compartment. Using CD31 to divide the naive CD4+ T-cells into CD27+CD45RA+CD31+ and CD27+CD45RA+CD31- subpopulations, we have shown that HIV-1 infection is associated with an accelerated decline in (a) the absolute number of cells within both subsets (b) telomere length within both subsets, and (c) telomerase activity within the CD27+CD45RA+CD31+ subset. Indeed, by these criteria, the naive CD4+ T-cell compartment in HIV-1 infected, ART naive, men closely resembles that of seronegative men 20 to 30 years their senior. Although the CD27+CD45RA+CD31+ population represents the naive CD4+ T-cell subset with the least proliferative history, telomere shortening in this subset is significant, suggesting that mechanisms other than increased T-cell turnover may be operative. If, as in aging, the shorter telomeres correlate with decreased functional capacity, the senescence of the naive CD4+ T-cell compartment may have a profound impact on the ability of the individual to mount effective immune responses, not only to HIV-1, but also to other pathogens, as well as vaccines and neoplasms. Moreover, if the well-documented age-related deficits in naive CD4+ T-cells synergizes with the effects of HIV- 1 infection on this compartment, as suggested by our preliminary data, this may contribute to the observed increased rate of disease progression in older persons. If not reversed by ART, these defects could also have important implications for the successful aging of HIV-1 infected, ART treated, individuals. The proposed studies will provide a more comprehensive understanding of the functional significance of the shorter telomeres in this naive CD4+ T-cell compartment (Aim 1) the mechanisms behind this shortening (Aim 2) and the potential for ART to reverse these defects (Aim 3). PUBLIC HELATH RELEVANCE: By understanding how age and HIV-1 impact the immune system, we may identify mechanisms of aging that can be targeted by therapeutic strategies increasing the health of both HIV-1 infected individuals and the elderly.